Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Converged Epitranscriptomic Co-regulation of TGFβ Signaling Components Suppresses the Quiescence Transition of Early Postnatal Hippocampal Neural Stem Cells

ABSTRACT: Quiescence acquisition of proliferating neural stem cells (NSCs) is required to establish the adult NSC pool yet the underlying molecular mechanisms are not well-understood. Here we showed that conditional deletion of the m6A reader Ythdf2, which promotes mRNA decay, in proliferating NSCs in the early postnatal mouse hippocampus led to elevated quiescence acquisition with decreased neurogenesis. Multimodal profiling of m6A modification, YTHDF2 binding, and mRNA decay in hippocampal NSCs identified shared targets in multiple TGFβ signaling pathway components, including TGFβ ligands, maturation factors, receptors, transcription regulators, and signaling regulators. Functionally, Ythdf2 deletion led to TGFβ signaling activation in NSCs, suppression of which rescued elevated quiescence acquisition of proliferating hippocampal NSCs. Our study reveals the dynamic nature and critical roles of mRNA decay in establishing the quiescent adult hippocampal NSC pool and uncovers a novel mode of epitranscriptomic control via co-regulation of multiple components of the same signaling pathway.

ORGANISM(S): Mus musculus

PROVIDER: GSE266096 | GEO | 2024/08/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Molecular Cascade Reveals Sequential Milestones Underlying Hippocampal Neural Stem Cell Development into an Adult State

Project description:Quiescent adult neural stem cells (NSCs) in the mammalian brain arise from proliferating NSCs during development. Beyond acquisition of quiescence, an adult NSC hallmark, little is known about the process, milestones and mechanisms underlying the transition of developmental NSCs to an adult NSC state. Here we performed targeted single-cell RNA-seq analysis to reveal the molecular cascade underlying NSC development in the early postnatal mouse dentate gyrus. We identified two sequential steps, first a transition to quiescence followed by further maturation, each of which involved distinct changes in metabolic gene expression. Direct metabolic analysis uncovered distinct milestones, including an autophagy burst before NSC quiescence acquisition and cellular ROS level elevation along NSC maturation. Functionally, autophagy is important for the NSC transition to quiescence during early postnatal development. Together, our study reveals a multi-step process with defined milestones underlying establishment of the adult NSC pool in the mammalian brain.

2024-06-05 | GSE232833 | GEO

Early Stem Cell Aging in the Mature Brain

Project description:Stem cell dysfunction drives many age-related disorders. Identifying mechanisms that initially compromise stem cell behavior represent early targets to enhance stem cell function later in life. Here, we pinpoint multiple factors that disrupt neural stem cell (NSC) behavior in the adult hippocampus. Clonal tracing showed that NSCs exhibit asynchronous depletion by identifying short-term (ST-NSC) and long-term NSCs (LT-NSCs). ST-NSC divide rapidly to generate neurons and deplete in the young brain. Meanwhile, multipotent LT-NSCs are maintained for months, but are pushed out of homeostasis by lengthening quiescence. Single cell transcriptome analysis of deep NSC quiescence revealed several hallmarks of molecular aging in the mature brain and identified tyrosine-protein kinase Abl1 as an NSC pro-aging factor. Treatment with the Abl-inhibitor Imatinib increased NSC proliferation without impairing NSC maintenance in the middle-aged brain. Our study indicates that hippocampal NSCs are particularly vulnerable to cellular aging, yet NSC function can be partially restored.

2021-03-03 | GSE168031 | GEO

Intracrine Vascular Endothelial Growth Factor Maintains Hippocampal Neural Stem Cell Quiescence

Project description:In the dentate gyrus (DG) of the adult mouse hippocampus, neural stem cells (NSCs) balance self-renewal and differentiation to produce neurons that support hippocampal function. Vascular endothelial growth factor (VEGF) is a well-known supporting factor for adult neurogenesis, but conflicting studies have left it uncertain how VEGF signals to NSCs. Here, we identified a VEGF-VEGFR2 intracrine signaling mechanism within adult DG NSCs that prevents their exhaustion. We show both in vitro and in vivo that NSC-VEGF loss caused cell-autonomous exhaustion of adult DG NSCs. In contrast, extracellular VEGF was neither necessary nor sufficient to maintain NSC quiescence or to stimulate VEGFR2 signaling, most likely due to sheddase-mediated cleavage of extracellular VEGFR2 ligand binding domains. Our findings support an exclusively intracellular mechanism for VEGF signaling in adult DG NSCs, thereby providing resolution to previously conflicting studies and suggesting cellular source can dictate the functional impact of soluble ligands in DG NSCs.

2024-04-16 | GSE220871 | GEO

Novel roles of small extracellular vesicles in regulating the quiescence and proliferation of neural stem cells

Project description:We analyzed protein cargos of NSC sEVs from proliferating, resting and reactivating status by proteomics approaches. Our results revealed specific functional clusters of pathways in gene ontology annotations of differentially expressed proteins in three sources of exosomes. Furthermore, we showed the involvement of sEVs in maintaining quiescence, along with entering and exiting the G0 phase by applying an exosome inhibitor. Our findings highlighted the expression level changes of NSCs of sEV protein cargo at different proliferative conditions and further confirmed the involvement of sEVs in entering, maintaining and exiting quiescence of NSCs.

2021-10-27 | PXD027651 | JPOST Repository

Rb family proteins are master regulators of the molecular signatures instructing the quiescent and activated adult neural stem cell state

Project description:The long-term maintenance of the adult neurogenic niche and neurogenesis is dependent on the proper regulation of entry and exit from quiescence. The dynamic transition from quiescence to activation is a complex process requiring not only precise cell cycle control, but also a co-ordinated phenotypic transition involving transcriptional and morphological changes. Presently, the mechanisms by which such a complex repertoire of factors interact and co-ordinate with the core cell cycle machinery to mediate these critical NSC fate transitions remains unknown. Here we show that the Rb/E2F axis functions as an on-off switch for NSC quiescence and activation, by linking the cell cycle machinery to pivotal regulators of NSC fate. Compound deletion of Rb family proteins results in massive activation and expansion of NSCs, and induces a global transcriptomic transition towards NSC activation followed by niche depletion. Deletion of their target activator E2Fs1/3 results in the failure of NSCs to become activated and the acquisition of a global transcriptome associated with intractable NSC quiescence and the cessation of adult neurogenesis. We further show that the Rb/E2F axis orchestrates these fate transitions through the direct regulation of factors essential to NSC function, including REST and ASCL1. This places the Rb/E2F axis as a master regulator of NSC fate, coordinating cell cycle control with NSC activation and quiescence fate transitions.

2022-11-01 | GSE190765 | GEO

Activator E2F family transcription factors are master regulators of the molecular signatures instructing the quiescent and activated adult neural stem cell state

2022-11-01 | GSE190764 | GEO

Troy+ brain stem cells cycle through quiescence and regulate their number by sensing niche occupancy

Project description:The adult mouse subependymal zone (SEZ) provides a niche for mammalian neural stem cells (NSCs). However, the molecular signature, self-renewal potential and fate behavior of NSCs remain poorly defined. Here we propose a model in which the fate of active NSCs is coupled to the total number of neighboring NSCs in a shared niche. Using knock-in reporter alleles and single-cell RNA sequencing, we show that the Wnt target Tnfrsf19/Troy identifies both active and quiescent NSCs. Quantitative analysis of genetic lineage tracing of individual NSCs under homeostasis or in response to injury reveals rapid expansion of stem cell number before some return to quiescence. This behavior is best explained by stochastic fate decisions, where stem cell number within a shared niche fluctuates over time. Fate-mapping proliferating cells using a novel Ki67iresCreER allele confirms that active NSCs reversibly return to quiescence, achieving long-term self-renewal. Our findings suggest a novel niche-based mechanism for the regulation of NSC fate and number.

2018-01-12 | GSE65970 | GEO

SETD4 Cells Contribute to Brain Development and Maintain Adult Stem Cell Reservoir for Neurogenesis

Project description:Cellular quiescence facilitates maintenance of neural stem cells (NSCs) and their subsequent regenerative functions in response to brain injury and aging. However, the specification and maintenance of NSCs in quiescence from embryo to adulthood remains largely unclear. Here, using Set domain-containing protein 4 (SETD4), an epigenetic determinant of cellular quiescence, we mark a small but long-lived NSC population in deep quiescence in the subventricular zone of adult murine brain. Genetic lineage tracing shows that SETD4+ cells appear before neuroectoderm formation and contribute to brain development. In the adult, conditional knock-out of SETD4 resulted in quiescence exit of NSCs, generating newborn neurons in the olfactory bulb and contributing to damage repair. However, long period deletion of SETD4 lead to exhaustion of NSC reservoir or SETD4 overexpression caused quiescence entry of NSCs, leading to suppressed neurogenesis. This study reveals the existence of long-lived deep quiescent NSCs and their neurogenetic capacities beyond activation.

2022-08-25 | GSE200159 | GEO

Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain Injury

Project description:Heterogeneous pools of adult neural stem cells (NSCs) contribute to brain maintenance and regeneration after injury. The balance of NSC activation and quiescence, as well as the induction of lineage-specific transcription factors, may contribute to diversity of neuronal and glial fates. To identify molecular hallmarks governing these characteristics, we performed single-cell sequencing of an unbiased pool of adult subventricular zone NSCs. This analysis identified a discrete, dormant NSC subpopulation that already expresses distinct combinations of lineage-specific transcription factors during homeostasis. Dormant NSCs enter a primed-quiescent state before activation, which is accompanied by downregulation of glycolytic metabolism, Notch, and BMP signaling and a concomitant upregulation of lineage-specific transcription factors and protein synthesis. In response to brain ischemia, interferon gamma signaling induces dormant NSC subpopulations to enter the primed-quiescent state. This study unveils general principles underlying NSC activation and lineage priming and opens potential avenues for regenerative medicine in the brain. Single cell RNAseq of cells isolated from their in vivo niche in the subventricular zone, Striatum and Cortex during homeostasis as well as following ischemic injury. In total 272 single cells. (<WT>: homeostasis samples; <Ischemic_injured> and <Ischemic_injured_and_Interferon_gamma_knockout>: samples following ischemic injuried).

2015-07-31 | E-GEOD-67833 | biostudies-arrayexpress

Epigenetic and transcriptomic profiling of neural stem cells after midazolam exposure

Project description:Here we show that early-life exposure to midazolam (MDZ), a widely used drug in pediatric anesthesia, persistently alters chromatin accessibility and expression of quiescence-associated genes in neural stem cells (NSCs) in mouse hippocampus. The alterations led to a continuous restriction of NSC proliferation toward adulthood, resulting in reduction of neurogenesis associated with the impairment of hippocampal-dependent memory functions. Moreover, we found that voluntary exercise restored hippocampal neurogenesis accompanied by the normalization of MDZ-perturbed transcriptome and ameliorated declined cognitive ability in MDZ-exposed mice.

2021-08-29 | GSE166322 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data